Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity.
Isothiocyanates exert strong anticarcinogenic effects in a number of animal models of cancer, presumably by modulation of xenobiotic-metabolizing enzymes, such as by inhibition of cytochrome P-450 and/or by induction of phase II detoxifying enzymes. Here, we report that phenethyl isothiocyanate and other structurally related isothiocyanates, phenylmethyl isothiocyanate, phenylbutyl isothiocyanate, and phenylhexyl isothiocyanate, but not phenyl isothiocyanate induced apoptosis in HeLa cells in a time- and dose-dependent manner. Treatment with apoptosis-inducing concentrations of isothiocyanates also caused rapid and transient induction of caspase-3/CPP32-like activity. Furthermore, these isothiocyanates, except phenyl isothiocyanate, stimulated proteolytic cleavage of poly(ADP-ribose) polymerase, which followed the appearance of caspase activity and preceded DNA fragmentation. Pretreatment with a potent caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde inhibited isothiocyanate-induced caspase-3-like activity and apoptosis. These results suggest that isothiocyanates may induce apoptosis through a caspase-3-dependent mechanism. The induction of apoptosis by isothiocyanates may provide a distinct mechanism for their chemopreventive functions.
Yu
R
R
Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, 60607-7173, USA.
Mandlekar
S
S
Harvey
K J
KJ
Ucker
D S
DS
Kong
A N
AN
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013861:Thiocyanates / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D015853:Cysteine Proteinase Inhibitors; D017879:Isothiocyanates; D009363:Neoplasm Proteins; D009842:Oligopeptides; D013861:Thiocyanates; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C005441:phenylisothiocyanate; C073279:6-phenylhexyl isothiocyanate; C081629:4-phenylbutyl isothiocyanate; C058305:phenethyl isothiocyanate; C031403:benzyl isothiocyanate; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases